Infection with hepatitis B virus (HBV) is a major cause of liver disease worldwide and affects more than 1 million people in the United States. Hepatitis induced by hepatitis B virus infection is a complex and intricate process involving interactions of multiple host factors with the virus and/or the viral gene products. The HBV X (HBV) gene plays a crucial role in the life cycle and oncogenic potential of HBV. Since virus-host interactions are central to the pathogenesis of viral infection and host injury, this project aims to elucidate the cellular and molecular mechanisms of HBX-host interactions during HBV infection. Using a variety of molecular, biochemical and cellular techniques, our laboratory has identified the proteasome complex as a cellular target of HBX. The 26S proteasome complex is the predominant cellular factor which degrades cellular proteins in both ubiquitin-dependent and -independent pathways. It has been implicated in the regulation of a variety of transcriptional and cell cycle factors, cellular stress response, and antigen presentation. It is speculated that HBX, by affecting the functions of proteasome, may exert a pleotropic effect on the cells. Our laboratory is also conducting experiments to study the biological significance of this interaction in animal models. In particular, structural and functional interactions are being studied in transgenic mouse expressing HBX and infectious woodchuck model. Finally, experiments are under way to develop compounds designed to interfere with HBX-proteasome interaction as a novel antiviral approach.